Melas et al. BMC Gastroenterol (2021) 21:128 https://doi.org/10.1186/s12876-021-01664-1 CASE REPORT Whipple’s disease: the great masquerader—a high level of suspicion is the key to diagnosis Nikolaos Melas 1 , Rasjan Amin 2 , Paula Gyllemark 3,4 , Amil Haji Younes 1 and Sven Almer 5,6* Abstract Background: Whipple’s disease is a chronic infectious disease that primarily affects the small intestine, but several organs can simultaneously be involved. The disease is caused by a gram-positive bacterium called Tropheryma whip- plei. The disease is difficult to suspect because it is rare with unspecific and long-term symptoms; it can be lethal if not properly treated. Case presentation: We here present three patients who presented with a plethora of symptoms, mainly long-stand- ing seronegative arthritis and gastrointestinal symptoms in the form of diarrhea with blood, weight loss, fever, and lymphadenopathy. They were after extensive investigations diagnosed with Whipple’s disease, in two of them as long as 8 years after the first occurrence of joint manifestations. The diagnosis was made by PCR targeting the T. whipplei 16S rRNA gene from small bowel specimen in all three patients, and, besides from histopathologic findings from the duodenum and distal ileum in one and mesenteric lymph nodes in another patient. Conclusions: This report aims to raise awareness of a very rare disease that presents with a combination of symp- toms mimicking other and significantly more common diseases. Keywords: Whipple’s disease, Tropheryma whipplei, Arthritis, Gastrointestinal symptoms © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Whipple’s disease (WD) is an infectious disease caused by the gram-positive bacterium Tropheryma whipplei. e first case was presented in 1907 by the pathologist George Hoyt Whipple [1] who named the disease lipo- dystrophy based on storage of fat in the intestinal wall and lymph nodes found at autopsy of a 36-year-old physi- cian who died after chronic joint problems, diarrhea and weight loss [2]. An infectious etiology was first discov- ered in 1961 by electron microscopy [3]. In 1991, Wilson et al. used polymerase chain reaction (PCR) which clas- sified the bacterium within Actinomyces [4]. It was not until 2000 that isolation and cultivation of a strain of T. whipplei were reported from the heart valve of a patient with blood culture-negative endocarditis [5]. ere are few studies on the prevalence and incidence of the disease. In a recent study from Italy, the prevalence was estimated to be 3 per 1,000,000 people [6]. Most cases are reported from North America and Europe. According to one study of 664 patients from the United States, 86% of cases occurred in men, 98% were of Cau- casian origin, with an average age at diagnosis of 49 years [7]. Most of the patients were farmers with occupational exposure to soil or animals. In a German study, the per- centage of women was higher, 22%, with a median age of 51 at the time of diagnosis [8]. e bacterium has been isolated in water, indicating that a non-fecal pathway of infection is presumed [5]. After contact with the bacterium, humans can become asymptomatic carriers of T. whipplei [9]. A genetic pre- disposition is often required to develop the disease, especially in CD11b-circulating lymphocytes which play a vital role in activating macrophages that phagocyte T. Open Access *Correspondence: [email protected] 5 Department of Medicine, Karolinska Institutet, Solna, Sweden Full list of author information is available at the end of the article
Whipple’s disease: the great masquerader—a high level of suspicion is the key to diagnosis
Dec 20, 2022
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Whipple's disease: the great masquerader—a high level of suspicion is the key to diagnosisCASE REPORT
Whipple’s disease: the great masquerader—a high level of suspicion is the key to diagnosis Nikolaos Melas1 , Rasjan Amin2, Paula Gyllemark3,4, Amil Haji Younes1 and Sven Almer5,6*
Abstract
Background: Whipple’s disease is a chronic infectious disease that primarily affects the small intestine, but several organs can simultaneously be involved. The disease is caused by a gram-positive bacterium called Tropheryma whip- plei. The disease is difficult to suspect because it is rare with unspecific and long-term symptoms; it can be lethal if not properly treated.
Case presentation: We here present three patients who presented with a plethora of symptoms, mainly long-stand- ing seronegative arthritis and gastrointestinal symptoms in the form of diarrhea with blood, weight loss, fever, and lymphadenopathy. They were after extensive investigations diagnosed with Whipple’s disease, in two of them as long as 8 years after the first occurrence of joint manifestations. The diagnosis was made by PCR targeting the T. whipplei 16S rRNA gene from small bowel specimen in all three patients, and, besides from histopathologic findings from the duodenum and distal ileum in one and mesenteric lymph nodes in another patient.
Conclusions: This report aims to raise awareness of a very rare disease that presents with a combination of symp- toms mimicking other and significantly more common diseases.
Keywords: Whipple’s disease, Tropheryma whipplei, Arthritis, Gastrointestinal symptoms
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Background Whipple’s disease (WD) is an infectious disease caused by the gram-positive bacterium Tropheryma whipplei. The first case was presented in 1907 by the pathologist George Hoyt Whipple [1] who named the disease lipo- dystrophy based on storage of fat in the intestinal wall and lymph nodes found at autopsy of a 36-year-old physi- cian who died after chronic joint problems, diarrhea and weight loss [2]. An infectious etiology was first discov- ered in 1961 by electron microscopy [3]. In 1991, Wilson et al. used polymerase chain reaction (PCR) which clas- sified the bacterium within Actinomyces [4]. It was not until 2000 that isolation and cultivation of a strain of T. whipplei were reported from the heart valve of a patient with blood culture-negative endocarditis [5].
There are few studies on the prevalence and incidence of the disease. In a recent study from Italy, the prevalence was estimated to be 3 per 1,000,000 people [6]. Most cases are reported from North America and Europe. According to one study of 664 patients from the United States, 86% of cases occurred in men, 98% were of Cau- casian origin, with an average age at diagnosis of 49 years [7]. Most of the patients were farmers with occupational exposure to soil or animals. In a German study, the per- centage of women was higher, 22%, with a median age of 51 at the time of diagnosis [8].
The bacterium has been isolated in water, indicating that a non-fecal pathway of infection is presumed [5]. After contact with the bacterium, humans can become asymptomatic carriers of T. whipplei [9]. A genetic pre- disposition is often required to develop the disease, especially in CD11b-circulating lymphocytes which play a vital role in activating macrophages that phagocyte T.
Open Access
*Correspondence: [email protected] 5 Department of Medicine, Karolinska Institutet, Solna, Sweden Full list of author information is available at the end of the article
Page 2 of 8Melas et al. BMC Gastroenterol (2021) 21:128
whipplei [9]. A link exists between the presence of HLA- B27 and the disease course [10].
The disease primarily affects the small intestine but several other organs may be involved, e.g. joints, brain, lungs, and heart. Whipple’s disease can be lethal if not treated. The natural course of classic WD is characterized by two stages. In a first, often long-lasting prodromal stage, three-quarters of patients experience non-specific symptoms, where arthritis is the first and most common manifestation [11]. In a second stage, the symptomatol- ogy is dominated by gastrointestinal manifestations, such as weight loss, nausea, and diarrhea. WD is therefore difficult to diagnose since it often has atypical manifes- tations and lymphadenopathy that lead to suspicion of lymphoma [12, 13]. The diagnosis is based on histopatho- logical examination of biopsies from the small bowel and PCR analysis of the 16S rRNA gene for T. whipplei [14].
Here, we report three patients with a delay of several years between the emergence of symptoms and the final diagnosis, aiming to raise the awareness of this unusual disease presenting with a combination of symptoms most often seen in far more common diseases and thereby these could be masqueraded.
Case presentation Patient 1 The patient was a 37-year-old Caucasian male, sporadic smoker, with moderate alcohol consumption, worked as a truck driver. Rheumatic symptoms had started 3 years before admission to hospital, with a transient swelling of one ring finger followed by intermittent episodes of fever with symmetrical and migratory pain, stiffness and in periods, swelling of several other joints. He was treated with non-steroidal and steroidal anti-inflammatory therapy due to palindromic rheumatism (PR) without improvement. The diagnosis was changed to seronega- tive rheumatoid arthritis (RA) and he was treated with methotrexate plus hydroxychloroquine. The joint stiff- ness continued while the swelling subsided.
Nine months later, he experienced gastrointestinal symptoms; flatulence, non-bloody diarrhea, sporadic vomiting, intermittent fever and slight weight loss. The body mass index (BMI) was 18.4 kg/m2 (initial 19.7 kg/ m2). Diarrhea gradually worsened with looser stool con- sistency, more frequent bowel emptying and abdominal pain. Anemia was detected with hemoglobin (Hb) of 120 g/L (normal range 134–170 g/L), hypoalbuminemia of 21 g/L (normal range 35–45 g/L). Stools were positive for hemoglobin and with an elevated level of calprotectin, 244 mg/kg (normal range 0–50 mg/kg). Anti-transglu- taminase antibodies were negative. The symptoms aggra- vated with water-thin diarrhea up to 30 times a day, the onset of fatigue, and B-symptoms such as night sweats
and fever peaks up to 40 degrees Celsius. A rectoscopy one month later was without pathological findings. By then, he had lost another 5 kg in weight (BMI 17 kg/m2) and was hospitalized. He underwent an abdominal com- puted tomography (CT) scan that showed signs of small bowel inflammation, why inflammatory bowel disease (IBD)—primarily Crohn’s disease—was suspected. He was given methotrexate 20 mg once a week and hydroxy- chloroquine 200 mg every morning. Laboratory exami- nations showed leukocytes 9.2 × 109/L, Hb 116 g/L, reticulocytes 24.6 × 109/L, platelet count 397 × 109/L, C-reactive protein (CRP) 19 mg/L, albumin 22 g/L and Erythrocyte Sedimentation Rate (ESR) 16 mm/h. Fecal cultures for Salmonella, Shigella, Yersinia, and Campy- lobacter were negative as was cytotoxin testing for Clostridium difficile. A second CT scan showed patho- logically enlarged lymph nodes extending paraaortically from upper abdomen down into the small pelvis and also ventrally in the mesentery. The working diagnosis was changed from IBD to malignant lymphoma and he was discharged from hospital and referred to oncological care. His condition deteriorated with significant fatigue, nausea, vomiting, and continued water-thin diarrhea 15–20 times per day with blood. He lost another 5 kg by weight (BMI 15.9 kg/m2).
The patient was again admitted and a colonoscopy performed, showing signs of relatively fresh bleeding and diffuse mucosal edema. Neither any evident bleed- ing source nor any signs of IBD were found. A diffusely swollen mucosa was seen in the distal ileum with abun- dant white-colored villi (Figs. 1, 2), which raised suspi- cion of WD. On histology of biopsies from ileum, light to moderate lymphoplasmatic cellular Periodic Acid-Schiff
Fig. 1 Colonoscopy. Distal ileum. Lumpy white-colored villi (see also histopathological Figs. 5 and 6) caused by ectatic lymphatic vessels that are histologically usually infiltrated by PAS-positive histiocytes. Patient 1
Page 3 of 8Melas et al. BMC Gastroenterol (2021) 21:128
(PAS)-positive infiltrate was present in the lamina pro- pria with an abundance of histiocytes; hence, a picture compatible with WD (Fig. 3). PCR for the 16S rRNA gene of T. whipplei from ileum was positive. Upper endoscopy revealed acute duodenitis with abundant narrow fibrin (Fig. 4). Duodenal biopsies showed similar findings as in the ileum, i.e. PAS-positive histiocytes with diastase- resistant granulated cytoplasm diagnostic for WD (Fig. 5) and positive PCR for the 16S rRNA gene of T. whipplei. Microscopy of an extirpated paraaortal lymph node was compatible with WD. Further PCR analyses for the 16S rRNA gene of T. whipplei were positive in serum but negative in the cerebrospinal fluid (CSF). Transthoracic
echocardiography (TTE) showed no signs of endocarditis or other abnormalities.
The patient was treated with ceftriaxone 2 g intrave- nously (IV) daily for two weeks with marked improve- ment already after three days. The diarrhea decreased, he began to support himself orally and gained 3.5 kg in weight. He was thereafter started on oral trimethoprim- sulfamethoxazole (TMP-SMX) 160 mg/800 mg twice a day for 1 year.
Three weeks after discharge from the hospital, the patient had gained an additional 3 kg with a BMI 15.8 kg/ m2. He was still weak, became easily fatigued, and was powerless and subfebrile. He had iron deficiency anemia and pronounced zinc and vitamin D deficiencies sec- ondary to malabsorption and received substitution. At 6 weeks after discharge, he was asymptomatic and had gained 7 kg in weight but was still slightly underweight with BMI 17.6 kg/m2. Six months after diagnosis, all lab- oratory values were normal; he had gained an additional 5 kg to BMI 18.9 kg/m2 and had taken up full-time work.
One and a half years after diagnosis, the patient was in good shape, had no symptoms, had normal weight and BMI. Upper endoscopy with duodenal biopsy was performed; histology was now normal and PCR for 16S rRNA was negative for T. whipplei. The treatment with TMP-SMX was discontinued after altogether 18 months.
Patient 2 A woman of Caucasian origin born in 1950, with a medi- cal history of nodular goiter, underwent thyroidectomy in 2002 and was given levothyroxine. She had been a regu- lar smoker until 1990, and later more sporadically. In 2007 she was seen in primary care because of morning
Fig. 2 Colonoscopy. Distal ileum. See text for Fig. 1
Fig. 3 Colonoscopy. Ileum. Clearly dilated lymphatic vessels in the villi (see also endoscopic Figs. 1 and 2) that make them white. Hematoxylin–eosin staining. 11x. Patient 1
Fig. 4 Gastroscopy. Duodenum. Diffuse mucosal redness with white-colored villi, especially abundant on folds where there are also longitudinal fibrin and hematine-coated ulcerations. Patient 1
Page 4 of 8Melas et al. BMC Gastroenterol (2021) 21:128
joint pain in her left hand which she had had from time to time during 8 years. The joint pain worsened and now also engaged the shoulders, right hip, and the back. Sym- metrical swelling of several metacarpophalangeal joints, of both wrists and knees was present. Repeated X-rays and magnetic resonance imaging (MRI) showed bursitis in the right hip and osteonecrosis. She was seen by many physicians and was given a diagnosis of PR, treated with hydroxychloroquine. Still, she experienced relapses and was trouble-free for a maximum of 2 weeks in-between. She had altogether tried eight anti-rheumatic drugs, however, all in suboptimal doses due to side effects or with insufficient effect. Her weight remained stable around 60 kg (BMI 22.9) until 2011 when she began to lose weight due to loss of appetite, malaise and gastroin- testinal discomfort.
In June 2014, her condition deteriorated with symp- toms of food aversion, night sweats, and fever. She lost a total of 12 kg (BMI 18.3) over 1 year. She was under treatment with methotrexate, and, since February 2013, in combination with adalimumab. A work-up with upper endoscopy showed gastritis and normal duodenal mucosa with unremarkable histology. Anti-transglutam- inase antibodies were negative. Colonoscopy showed sigmoid diverticulosis but nothing that could explain the symptoms.
Malignant lymphoma was suspected and an abdom- inal CT-scan showed panniculitis. Bone marrow examination was without any signs of lymphoma. In November 2014, a new rheumatologic assessment considered her to be low active in her RA. Blood tests
showed elevated CRP, ESR, and leukocytes, and, when treatment was intensified, the fever came back. Sero- logical analyses regarding HIV, hepatitis B and C, Epstein-Barr virus (EBV), cytomegalovirus (CMV), parvovirus B19, and tick-borne encephalitis virus were all negative. MRI of the small bowel confirmed two cm- large mesenterial lymph nodes related to panniculitis. Gynecological examination and mammography were unremarkable. Tumor markers CA19-9, CA15-3, and CEA were within normal limits, CA-125 was slightly elevated. A Positron Emission Tomography-Computed Tomography (PET-CT) could not explain the increased inflammatory burden or the new symptoms.
In June 2015 the patient was referred for a second opinion. A new upper endoscopy was performed with biopsy from the duodenum. On histology, infiltration of polymorph nuclear granulocytes into lamina propria was seen along with mild cryptitis. PAS staining was nega- tive without aberrant macrophages or any other findings compatible with WD. PCR for T. whipplei was positive.
Treatment started in October 2015 with ceftriaxone 2 g IV once a day for 14 days followed by TMP-SMX 800/160 mg twice a day. After 4 weeks abdominal and joint symptoms had disappeared and weight was regained. The sequential biologic therapy (infliximab, abatacept, and adalimumab) for 5.5 years was stopped. At three months the patient had normalized leukocytes, CRP, and ESR. Methotrexate treatment for 6 years was then stopped, and, within nine months after the start of antibiotics, 8 years of more or less continuous predni- solone use was no longer needed.
Fig. 5 Gastroscopy. Duodenum. In lamina propria, histiocytes with PAS (periodic acid-Shiff )-positive, diastase-resistant, granulated cytoplasm is seen. 11x. Patient 1
Page 5 of 8Melas et al. BMC Gastroenterol (2021) 21:128
During the following year, she suffered periods of scle- ritis, necessitating courses of prednisolone and localized joint pain with the need for local steroid injections in the shoulders, in the left acromioclavicular joint, or in the right hip where an x-ray was compatible with arthrosis. Due to nausea and bowel upset, TMP-SMX was replaced by doxycycline after six months. After 13 months of anti- biotic treatment, variable abdominal symptoms appeared which led to an upper endoscopy due to suspicion of dis- ease relapse. The gastric and duodenal mucosa was nor- mal without PAS-positive cells and negative PCR for T. whipplei. A CT scan after 2 years of antibiotics showed marked regression of the abdominal lymph nodes. Doxy- cycline was stopped at the end of December 2017 after altogether 27 months of antibiotic treatment.
A follow-up investigation at 3 years after diagnosis including testing for fecal blood and microbes, and upper endoscopy with biopsy, was negative. Repeated tests for fecal blood and calprotectin between 2015 and 2020 have all been negative. Five years after diagnosis (September 2020) the patient is doing well, she has only mild, non- specific abdominal and joint symptoms, and persisting mild polyneuropathy in feet and ankles.
Patient 3 A 52-year-old Caucasian male was in the summer of 2018 referred to hospital with a 2-year history of 12 kg weight loss, recurrent low-grade fever, night sweats, and fatigue. He worked as an industrial worker, and had a history of regular visits to Brazil, mostly for sunbathing. Previous medical history included lower back pain with a herni- ated lumbar disc.
A CT-scan of the thorax and abdomen showed multiple para-aortic enlarged lymph nodes and borderline spleno- megaly. The ascending aorta was slightly dilated which was confirmed by a TTE. His back pain was worsening. Laboratory results showed ESR 40 mm/h, CRP 40 mg/L, albumin 35 g/L, and Hb 130 g/L. Serology regarding EBV and CMV was positive for IgG, i.e. reflecting past infection. Serology for HIV, Q fever (Coxiella burnettii), Leishmania, Brucella, Bartonella henselae, Bartonella quintana, and Trypanosoma cruzi were all negative as was an interferon-gamma release assay and two sets of aerobic and anaerobic blood cultures.
The investigation could not find any evidence of infec- tious disease. A bone marrow biopsy showed signs of reactive cells but no malignant cells. A CT-guided medium needle biopsy on the para-aortic lymph nodes excluded malignancy and displayed only increased num- bers of B and T lymphocytes. Immunohistochemical analysis showed numerous CD68 positive cells. MRI of the vertebral column showed an unchanged slightly her- niated disc.
Symptoms remained unaltered and more than 1 year later, a new CT of the abdomen showed increased retro- peritoneal lymph node enlargement (Fig. 6). At abdomi- nal laparoscopy, three intact lymph nodes were extracted. Numerous lymphocytes, as well as many giant lym- phocytes and macrophages, were found, the latter with positive PAS staining. The patient underwent upper endoscopy where the mucosa was normal and routine staining of duodenal biopsies was normal and PCR for T. whipplei was positive.
The patient was treated for 2 weeks with ceftri- axone (2 g IV once a day) followed by TMP-SMX 160 mg/800 mg, twice a day, planned for 1 year. Symp- toms gradually disappeared within a couple of weeks, including the low back pain. After four months of treat- ment ESR, CRP, and Hb had normalized. No drug- induced side effects have occurred during 12 months of treatment.
Discussion and conclusions We report three patients with WD, with a delay of sev- eral years between the appearance of unspecific, mainly rheumatic, symptoms, and the final diagnosis. The clas- sic onset symptom is joint discomfort in 80% of patients which precedes other symptoms. Predominantly large joints (knees, wrists, and ankles) are affected with migra- tory arthralgia/arthritis. Many patients are initially diag- nosed with seronegative RA, and, according to a French
Fig. 6 Coronal CT showing enlarged lymph nodes in the small bowel mesentery (white arrows). All of them have very low attenuation suggesting fat content which is common in Whipple’s disease, Patient 3
Page 6 of 8Melas et al. BMC Gastroenterol (2021) 21:128
study, half of them receive immunomodulatory therapy, including anti-TNF-α [16]. It is reported that antirheu- matic drugs can worsen the course of the disease with gastrointestinal symptoms, prompting investigation with endoscopy as demonstrated by the disease evolution to patient two, with the appearance of abdominal symptoms during the year following the addition of adalimumab treatment [17].
Several characteristic similarities were seen in Patients one and two. They both had very long arthritic phases before obvious gastrointestinal symptoms appeared and led to the correct diagnosis. They were initially diagnosed as PR and had been on long-term corticosteroid and immunosuppressive therapy. Treatment with anti-TNF-α can paradoxically reveal and/or aggravate the disease, especially etanercept (Patient two), or in combination with other disease-modifying antirheumatic drugs, usu- ally methotrexate and corticosteroids [18]. Although Patient three had symptoms of a more systemic nature and did not present joint symptoms with the need for immunosuppressive therapy, there are still similarities between all three patients. They had laboratory find- ings with unexplained anemia, leucocytosis, hypoalbu- minemia, plus enlarged mesenterial lymph nodes, and B-symptoms with a strong suspicion of lymphoma [16], which prompted further investigations with bone mar- row biopsy and lymph node extirpation. Since WD affects different organ systems, and present several more or less unspecific symptoms [15], we want to underline the similarities…
Whipple’s disease: the great masquerader—a high level of suspicion is the key to diagnosis Nikolaos Melas1 , Rasjan Amin2, Paula Gyllemark3,4, Amil Haji Younes1 and Sven Almer5,6*
Abstract
Background: Whipple’s disease is a chronic infectious disease that primarily affects the small intestine, but several organs can simultaneously be involved. The disease is caused by a gram-positive bacterium called Tropheryma whip- plei. The disease is difficult to suspect because it is rare with unspecific and long-term symptoms; it can be lethal if not properly treated.
Case presentation: We here present three patients who presented with a plethora of symptoms, mainly long-stand- ing seronegative arthritis and gastrointestinal symptoms in the form of diarrhea with blood, weight loss, fever, and lymphadenopathy. They were after extensive investigations diagnosed with Whipple’s disease, in two of them as long as 8 years after the first occurrence of joint manifestations. The diagnosis was made by PCR targeting the T. whipplei 16S rRNA gene from small bowel specimen in all three patients, and, besides from histopathologic findings from the duodenum and distal ileum in one and mesenteric lymph nodes in another patient.
Conclusions: This report aims to raise awareness of a very rare disease that presents with a combination of symp- toms mimicking other and significantly more common diseases.
Keywords: Whipple’s disease, Tropheryma whipplei, Arthritis, Gastrointestinal symptoms
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Background Whipple’s disease (WD) is an infectious disease caused by the gram-positive bacterium Tropheryma whipplei. The first case was presented in 1907 by the pathologist George Hoyt Whipple [1] who named the disease lipo- dystrophy based on storage of fat in the intestinal wall and lymph nodes found at autopsy of a 36-year-old physi- cian who died after chronic joint problems, diarrhea and weight loss [2]. An infectious etiology was first discov- ered in 1961 by electron microscopy [3]. In 1991, Wilson et al. used polymerase chain reaction (PCR) which clas- sified the bacterium within Actinomyces [4]. It was not until 2000 that isolation and cultivation of a strain of T. whipplei were reported from the heart valve of a patient with blood culture-negative endocarditis [5].
There are few studies on the prevalence and incidence of the disease. In a recent study from Italy, the prevalence was estimated to be 3 per 1,000,000 people [6]. Most cases are reported from North America and Europe. According to one study of 664 patients from the United States, 86% of cases occurred in men, 98% were of Cau- casian origin, with an average age at diagnosis of 49 years [7]. Most of the patients were farmers with occupational exposure to soil or animals. In a German study, the per- centage of women was higher, 22%, with a median age of 51 at the time of diagnosis [8].
The bacterium has been isolated in water, indicating that a non-fecal pathway of infection is presumed [5]. After contact with the bacterium, humans can become asymptomatic carriers of T. whipplei [9]. A genetic pre- disposition is often required to develop the disease, especially in CD11b-circulating lymphocytes which play a vital role in activating macrophages that phagocyte T.
Open Access
*Correspondence: [email protected] 5 Department of Medicine, Karolinska Institutet, Solna, Sweden Full list of author information is available at the end of the article
Page 2 of 8Melas et al. BMC Gastroenterol (2021) 21:128
whipplei [9]. A link exists between the presence of HLA- B27 and the disease course [10].
The disease primarily affects the small intestine but several other organs may be involved, e.g. joints, brain, lungs, and heart. Whipple’s disease can be lethal if not treated. The natural course of classic WD is characterized by two stages. In a first, often long-lasting prodromal stage, three-quarters of patients experience non-specific symptoms, where arthritis is the first and most common manifestation [11]. In a second stage, the symptomatol- ogy is dominated by gastrointestinal manifestations, such as weight loss, nausea, and diarrhea. WD is therefore difficult to diagnose since it often has atypical manifes- tations and lymphadenopathy that lead to suspicion of lymphoma [12, 13]. The diagnosis is based on histopatho- logical examination of biopsies from the small bowel and PCR analysis of the 16S rRNA gene for T. whipplei [14].
Here, we report three patients with a delay of several years between the emergence of symptoms and the final diagnosis, aiming to raise the awareness of this unusual disease presenting with a combination of symptoms most often seen in far more common diseases and thereby these could be masqueraded.
Case presentation Patient 1 The patient was a 37-year-old Caucasian male, sporadic smoker, with moderate alcohol consumption, worked as a truck driver. Rheumatic symptoms had started 3 years before admission to hospital, with a transient swelling of one ring finger followed by intermittent episodes of fever with symmetrical and migratory pain, stiffness and in periods, swelling of several other joints. He was treated with non-steroidal and steroidal anti-inflammatory therapy due to palindromic rheumatism (PR) without improvement. The diagnosis was changed to seronega- tive rheumatoid arthritis (RA) and he was treated with methotrexate plus hydroxychloroquine. The joint stiff- ness continued while the swelling subsided.
Nine months later, he experienced gastrointestinal symptoms; flatulence, non-bloody diarrhea, sporadic vomiting, intermittent fever and slight weight loss. The body mass index (BMI) was 18.4 kg/m2 (initial 19.7 kg/ m2). Diarrhea gradually worsened with looser stool con- sistency, more frequent bowel emptying and abdominal pain. Anemia was detected with hemoglobin (Hb) of 120 g/L (normal range 134–170 g/L), hypoalbuminemia of 21 g/L (normal range 35–45 g/L). Stools were positive for hemoglobin and with an elevated level of calprotectin, 244 mg/kg (normal range 0–50 mg/kg). Anti-transglu- taminase antibodies were negative. The symptoms aggra- vated with water-thin diarrhea up to 30 times a day, the onset of fatigue, and B-symptoms such as night sweats
and fever peaks up to 40 degrees Celsius. A rectoscopy one month later was without pathological findings. By then, he had lost another 5 kg in weight (BMI 17 kg/m2) and was hospitalized. He underwent an abdominal com- puted tomography (CT) scan that showed signs of small bowel inflammation, why inflammatory bowel disease (IBD)—primarily Crohn’s disease—was suspected. He was given methotrexate 20 mg once a week and hydroxy- chloroquine 200 mg every morning. Laboratory exami- nations showed leukocytes 9.2 × 109/L, Hb 116 g/L, reticulocytes 24.6 × 109/L, platelet count 397 × 109/L, C-reactive protein (CRP) 19 mg/L, albumin 22 g/L and Erythrocyte Sedimentation Rate (ESR) 16 mm/h. Fecal cultures for Salmonella, Shigella, Yersinia, and Campy- lobacter were negative as was cytotoxin testing for Clostridium difficile. A second CT scan showed patho- logically enlarged lymph nodes extending paraaortically from upper abdomen down into the small pelvis and also ventrally in the mesentery. The working diagnosis was changed from IBD to malignant lymphoma and he was discharged from hospital and referred to oncological care. His condition deteriorated with significant fatigue, nausea, vomiting, and continued water-thin diarrhea 15–20 times per day with blood. He lost another 5 kg by weight (BMI 15.9 kg/m2).
The patient was again admitted and a colonoscopy performed, showing signs of relatively fresh bleeding and diffuse mucosal edema. Neither any evident bleed- ing source nor any signs of IBD were found. A diffusely swollen mucosa was seen in the distal ileum with abun- dant white-colored villi (Figs. 1, 2), which raised suspi- cion of WD. On histology of biopsies from ileum, light to moderate lymphoplasmatic cellular Periodic Acid-Schiff
Fig. 1 Colonoscopy. Distal ileum. Lumpy white-colored villi (see also histopathological Figs. 5 and 6) caused by ectatic lymphatic vessels that are histologically usually infiltrated by PAS-positive histiocytes. Patient 1
Page 3 of 8Melas et al. BMC Gastroenterol (2021) 21:128
(PAS)-positive infiltrate was present in the lamina pro- pria with an abundance of histiocytes; hence, a picture compatible with WD (Fig. 3). PCR for the 16S rRNA gene of T. whipplei from ileum was positive. Upper endoscopy revealed acute duodenitis with abundant narrow fibrin (Fig. 4). Duodenal biopsies showed similar findings as in the ileum, i.e. PAS-positive histiocytes with diastase- resistant granulated cytoplasm diagnostic for WD (Fig. 5) and positive PCR for the 16S rRNA gene of T. whipplei. Microscopy of an extirpated paraaortal lymph node was compatible with WD. Further PCR analyses for the 16S rRNA gene of T. whipplei were positive in serum but negative in the cerebrospinal fluid (CSF). Transthoracic
echocardiography (TTE) showed no signs of endocarditis or other abnormalities.
The patient was treated with ceftriaxone 2 g intrave- nously (IV) daily for two weeks with marked improve- ment already after three days. The diarrhea decreased, he began to support himself orally and gained 3.5 kg in weight. He was thereafter started on oral trimethoprim- sulfamethoxazole (TMP-SMX) 160 mg/800 mg twice a day for 1 year.
Three weeks after discharge from the hospital, the patient had gained an additional 3 kg with a BMI 15.8 kg/ m2. He was still weak, became easily fatigued, and was powerless and subfebrile. He had iron deficiency anemia and pronounced zinc and vitamin D deficiencies sec- ondary to malabsorption and received substitution. At 6 weeks after discharge, he was asymptomatic and had gained 7 kg in weight but was still slightly underweight with BMI 17.6 kg/m2. Six months after diagnosis, all lab- oratory values were normal; he had gained an additional 5 kg to BMI 18.9 kg/m2 and had taken up full-time work.
One and a half years after diagnosis, the patient was in good shape, had no symptoms, had normal weight and BMI. Upper endoscopy with duodenal biopsy was performed; histology was now normal and PCR for 16S rRNA was negative for T. whipplei. The treatment with TMP-SMX was discontinued after altogether 18 months.
Patient 2 A woman of Caucasian origin born in 1950, with a medi- cal history of nodular goiter, underwent thyroidectomy in 2002 and was given levothyroxine. She had been a regu- lar smoker until 1990, and later more sporadically. In 2007 she was seen in primary care because of morning
Fig. 2 Colonoscopy. Distal ileum. See text for Fig. 1
Fig. 3 Colonoscopy. Ileum. Clearly dilated lymphatic vessels in the villi (see also endoscopic Figs. 1 and 2) that make them white. Hematoxylin–eosin staining. 11x. Patient 1
Fig. 4 Gastroscopy. Duodenum. Diffuse mucosal redness with white-colored villi, especially abundant on folds where there are also longitudinal fibrin and hematine-coated ulcerations. Patient 1
Page 4 of 8Melas et al. BMC Gastroenterol (2021) 21:128
joint pain in her left hand which she had had from time to time during 8 years. The joint pain worsened and now also engaged the shoulders, right hip, and the back. Sym- metrical swelling of several metacarpophalangeal joints, of both wrists and knees was present. Repeated X-rays and magnetic resonance imaging (MRI) showed bursitis in the right hip and osteonecrosis. She was seen by many physicians and was given a diagnosis of PR, treated with hydroxychloroquine. Still, she experienced relapses and was trouble-free for a maximum of 2 weeks in-between. She had altogether tried eight anti-rheumatic drugs, however, all in suboptimal doses due to side effects or with insufficient effect. Her weight remained stable around 60 kg (BMI 22.9) until 2011 when she began to lose weight due to loss of appetite, malaise and gastroin- testinal discomfort.
In June 2014, her condition deteriorated with symp- toms of food aversion, night sweats, and fever. She lost a total of 12 kg (BMI 18.3) over 1 year. She was under treatment with methotrexate, and, since February 2013, in combination with adalimumab. A work-up with upper endoscopy showed gastritis and normal duodenal mucosa with unremarkable histology. Anti-transglutam- inase antibodies were negative. Colonoscopy showed sigmoid diverticulosis but nothing that could explain the symptoms.
Malignant lymphoma was suspected and an abdom- inal CT-scan showed panniculitis. Bone marrow examination was without any signs of lymphoma. In November 2014, a new rheumatologic assessment considered her to be low active in her RA. Blood tests
showed elevated CRP, ESR, and leukocytes, and, when treatment was intensified, the fever came back. Sero- logical analyses regarding HIV, hepatitis B and C, Epstein-Barr virus (EBV), cytomegalovirus (CMV), parvovirus B19, and tick-borne encephalitis virus were all negative. MRI of the small bowel confirmed two cm- large mesenterial lymph nodes related to panniculitis. Gynecological examination and mammography were unremarkable. Tumor markers CA19-9, CA15-3, and CEA were within normal limits, CA-125 was slightly elevated. A Positron Emission Tomography-Computed Tomography (PET-CT) could not explain the increased inflammatory burden or the new symptoms.
In June 2015 the patient was referred for a second opinion. A new upper endoscopy was performed with biopsy from the duodenum. On histology, infiltration of polymorph nuclear granulocytes into lamina propria was seen along with mild cryptitis. PAS staining was nega- tive without aberrant macrophages or any other findings compatible with WD. PCR for T. whipplei was positive.
Treatment started in October 2015 with ceftriaxone 2 g IV once a day for 14 days followed by TMP-SMX 800/160 mg twice a day. After 4 weeks abdominal and joint symptoms had disappeared and weight was regained. The sequential biologic therapy (infliximab, abatacept, and adalimumab) for 5.5 years was stopped. At three months the patient had normalized leukocytes, CRP, and ESR. Methotrexate treatment for 6 years was then stopped, and, within nine months after the start of antibiotics, 8 years of more or less continuous predni- solone use was no longer needed.
Fig. 5 Gastroscopy. Duodenum. In lamina propria, histiocytes with PAS (periodic acid-Shiff )-positive, diastase-resistant, granulated cytoplasm is seen. 11x. Patient 1
Page 5 of 8Melas et al. BMC Gastroenterol (2021) 21:128
During the following year, she suffered periods of scle- ritis, necessitating courses of prednisolone and localized joint pain with the need for local steroid injections in the shoulders, in the left acromioclavicular joint, or in the right hip where an x-ray was compatible with arthrosis. Due to nausea and bowel upset, TMP-SMX was replaced by doxycycline after six months. After 13 months of anti- biotic treatment, variable abdominal symptoms appeared which led to an upper endoscopy due to suspicion of dis- ease relapse. The gastric and duodenal mucosa was nor- mal without PAS-positive cells and negative PCR for T. whipplei. A CT scan after 2 years of antibiotics showed marked regression of the abdominal lymph nodes. Doxy- cycline was stopped at the end of December 2017 after altogether 27 months of antibiotic treatment.
A follow-up investigation at 3 years after diagnosis including testing for fecal blood and microbes, and upper endoscopy with biopsy, was negative. Repeated tests for fecal blood and calprotectin between 2015 and 2020 have all been negative. Five years after diagnosis (September 2020) the patient is doing well, she has only mild, non- specific abdominal and joint symptoms, and persisting mild polyneuropathy in feet and ankles.
Patient 3 A 52-year-old Caucasian male was in the summer of 2018 referred to hospital with a 2-year history of 12 kg weight loss, recurrent low-grade fever, night sweats, and fatigue. He worked as an industrial worker, and had a history of regular visits to Brazil, mostly for sunbathing. Previous medical history included lower back pain with a herni- ated lumbar disc.
A CT-scan of the thorax and abdomen showed multiple para-aortic enlarged lymph nodes and borderline spleno- megaly. The ascending aorta was slightly dilated which was confirmed by a TTE. His back pain was worsening. Laboratory results showed ESR 40 mm/h, CRP 40 mg/L, albumin 35 g/L, and Hb 130 g/L. Serology regarding EBV and CMV was positive for IgG, i.e. reflecting past infection. Serology for HIV, Q fever (Coxiella burnettii), Leishmania, Brucella, Bartonella henselae, Bartonella quintana, and Trypanosoma cruzi were all negative as was an interferon-gamma release assay and two sets of aerobic and anaerobic blood cultures.
The investigation could not find any evidence of infec- tious disease. A bone marrow biopsy showed signs of reactive cells but no malignant cells. A CT-guided medium needle biopsy on the para-aortic lymph nodes excluded malignancy and displayed only increased num- bers of B and T lymphocytes. Immunohistochemical analysis showed numerous CD68 positive cells. MRI of the vertebral column showed an unchanged slightly her- niated disc.
Symptoms remained unaltered and more than 1 year later, a new CT of the abdomen showed increased retro- peritoneal lymph node enlargement (Fig. 6). At abdomi- nal laparoscopy, three intact lymph nodes were extracted. Numerous lymphocytes, as well as many giant lym- phocytes and macrophages, were found, the latter with positive PAS staining. The patient underwent upper endoscopy where the mucosa was normal and routine staining of duodenal biopsies was normal and PCR for T. whipplei was positive.
The patient was treated for 2 weeks with ceftri- axone (2 g IV once a day) followed by TMP-SMX 160 mg/800 mg, twice a day, planned for 1 year. Symp- toms gradually disappeared within a couple of weeks, including the low back pain. After four months of treat- ment ESR, CRP, and Hb had normalized. No drug- induced side effects have occurred during 12 months of treatment.
Discussion and conclusions We report three patients with WD, with a delay of sev- eral years between the appearance of unspecific, mainly rheumatic, symptoms, and the final diagnosis. The clas- sic onset symptom is joint discomfort in 80% of patients which precedes other symptoms. Predominantly large joints (knees, wrists, and ankles) are affected with migra- tory arthralgia/arthritis. Many patients are initially diag- nosed with seronegative RA, and, according to a French
Fig. 6 Coronal CT showing enlarged lymph nodes in the small bowel mesentery (white arrows). All of them have very low attenuation suggesting fat content which is common in Whipple’s disease, Patient 3
Page 6 of 8Melas et al. BMC Gastroenterol (2021) 21:128
study, half of them receive immunomodulatory therapy, including anti-TNF-α [16]. It is reported that antirheu- matic drugs can worsen the course of the disease with gastrointestinal symptoms, prompting investigation with endoscopy as demonstrated by the disease evolution to patient two, with the appearance of abdominal symptoms during the year following the addition of adalimumab treatment [17].
Several characteristic similarities were seen in Patients one and two. They both had very long arthritic phases before obvious gastrointestinal symptoms appeared and led to the correct diagnosis. They were initially diagnosed as PR and had been on long-term corticosteroid and immunosuppressive therapy. Treatment with anti-TNF-α can paradoxically reveal and/or aggravate the disease, especially etanercept (Patient two), or in combination with other disease-modifying antirheumatic drugs, usu- ally methotrexate and corticosteroids [18]. Although Patient three had symptoms of a more systemic nature and did not present joint symptoms with the need for immunosuppressive therapy, there are still similarities between all three patients. They had laboratory find- ings with unexplained anemia, leucocytosis, hypoalbu- minemia, plus enlarged mesenterial lymph nodes, and B-symptoms with a strong suspicion of lymphoma [16], which prompted further investigations with bone mar- row biopsy and lymph node extirpation. Since WD affects different organ systems, and present several more or less unspecific symptoms [15], we want to underline the similarities…
Related Documents
